Heart failure is the inability of the heart to meet hemodynamic demands and represents the end stage of various forms of cardiovascular disease. In industrialized nations, heart failure represents a major health problem that has been increasing in prevalence and incidence. It is estimated that 5.7 million people in the United States have heart failure resulting in about $37.2 billion being spent a year to cover associated health care related costs. Therefore, drug therapy designed to coincide with the standard means of care are needed to decrease the extent of injury leading to the development of heart failure. Recently, hydrogen sulfide (H2S) has been shown to be cardioprotective in various in vitro and in vivo models of cardiac injury. Although the physiological and cardioprotective effects of H2S in acute models of ischemia- reperfusion injury have previously been documented, the signaling mechanisms that mediate these effects have not been fully studied. Moreover, the signaling mechanisms that have been attributed to H2S have predominantly been studied in in vitro model systems, with very few studies actually exploring the protective effects in in vivo systems. Additionally, the cardioprotective effects of H2S in the setting of heart failure have not been investigated. For this reason, the studies proposed in this application are extremely important and timely. The overall aim of this proposal is to evaluate the signaling mechanisms responsible for the observed cardioprotective effects of H2S therapy in the setting of heart failure. To this end, the transcription factor, Nrf2, has been identified as a possible regulator of these cardioprotective effects. Therefore, the central hypothesis for the proposed studies is that H2S up-regulates endogenous antioxidants, alleviates mitochondrial dysfunction, and reduces hypertrophy in a Nrf2-dependent manner. To test this hypothesis, 3 Specific Aims have been proposed. Specific Aim 1 will evaluate the role of Nrf2 signaling in mediating the antioxidant effects of H2S. Specific Aim 2 will investigate if H2S suppresses apoptosis and cardiac hypertrophy via Nrf2/Trx1- dependent signaling. Specific Aim 3 will investigate if H2S induces mitochondrial biogenesis via Nrf2- dependent signaling. The proposed studies will significantly advance our current understanding of the mechanisms responsible for the development of heart failure and will answer important questions regarding the signaling mechanism responsible for the cardioprotective effects of H2S in the setting of heart failure. Additionally, information gained from these studies will provide the foundation for the development of H2S therapy for the treatment of heart failure. PUBLIC HEALTH RELEVANCE: Despite numerous advances in health care, cardiovascular disease remains the number one killer in the United States and heart failure, as a direct result of cardiovascular disease, affects nearly 5.3 million people in the United States resulting in about $34.8 billion being spent a year to cover associated health care related costs. The proposed studies will evaluate the efficacy of a hydrogen sulfide releasing compound in clinically relevant and highly translational experimental model systems of heart failure. The proposed studies will significantly advance our current understanding of the mechanisms responsible for the development of heart failure and will answer important questions regarding the signaling mechanism responsible for the cardioprotective effects of hydrogen sulfide in the setting of heart failure.